EU/3/07/514

Orphan designation

On 4 December 2007, orphan designation (EU/3/07/514) was granted by the European Commission to Genzyme Europe BV, Netherlands, for (1R,2R)-octanoic acid[2-(2',3'-dihydro-benzo[1,4] dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt for the treatment of Gaucher disease.

(1R,2R)-octanoic acid[2-(2',3'-dihydro-benzo[1,4] dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt has been authorised in the EU as Cerdelga since 19 January 2015.

Gaucher disease is characterized by the accumulation of specific chemical substances (glucocerebrosides) in several cells (macrophages and monocytes) that are localized throughout the body, but particularly in the spleen, liver and bone marrow. The disorder results from the decreased activity of an enzyme (a protein that stimulates a chemical reaction in the body), called glucocerebrosidase; this enzyme destroys the glucocerebrosides. Since glucocerebrosides are not destroyed, they progressively accumulate in the cells. The disorder has a genetic origin, so it is caused by damage in a gene that carries the information necessary for the production of the enzyme. Usually both parents are healthy carriers of a single copy of the damaged gene. To develop the disease, two damaged copies must be present in the same individual (this is called autosomal recessive inheritance). The severity of Gaucher disease is extremely variable; some patients show with virtually all the complications of Gaucher disease during childhood, while others remain asymptomatic for more than 70 years.

Gaucher disease has traditionally been divided into the following 3 clinical subtypes, according to the absence or presence of damage to the nerves and its progression:

Type 1 - Nonneuronopathic form (the most common and less severe form);

Type 2 - Acute neuronopathic form (the most severe form, usually diagnosed shortly after birth);

At the time of designation, Gaucher disease affected approximately 0.3 in 10,000 people in the European Union (EU). This was equivalent to a total of around 15,000 people*, and is below the ceiling for orphan designation, which is 5 people in 10,000. This isbased on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

*Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed on the basis of data from the European Union (EU 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 500,300,000 (Eurostat 2007).

At the time of the application for orphan designation, two medicinal products were authorized in the European Union for the treatment of Gaucher syndrome, miglustat (Zavesca, given orally) and imiglucerase (Cerezyme, given intravenously). Given its different mechanism of action, (1R,2R)-octanoic acid[2-(2',3'-dihydro-benzo[1,4] dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt may be of potential significant benefit over the currently authorised medicinal products. This assumption will have to be confirmed at the time of marketing authorisation, and this will be necessary to maintain the orphan status.

(1R,2R)-Octanoic acid[2-(2’,3’-dihydro-benzo [1,4] dioxin-6’-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt blocks the function of an enzyme called glucosylceramide synthase. This enzyme helps to build the substance that accumulates in Gaucher disease (the glucocerebrosides, which then cannot be eliminated because of the genetic defect in the enzyme that destroys them). Thus, by blocking the action of glucosylceramide synthase, the levels of glucocerebrosides in the body are reduced and its accumulation should also be reduced.

the existence of alternative methods of diagnosis, prevention or treatment;

either the rarity of the condition (affecting not more than 5 in 10,000 people in the EU) or insufficient returns on investment.

Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.

Review of designation

During its meeting of 9 to 11 December 2014, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/07/514 for Cerdelga (eliglustat)1 as an orphan medicinal product for the treatment of Gaucher disease. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other methods of treatment. As other methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with Gaucher disease. The COMP recommended that the orphan designation of the medicine be maintained2.

2The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with a comparable therapeutic indication cannot be placed on the market.

This falls within the scope of the product’s designated orphan indication, which is: ‘Gaucher disease’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2007. Gaucher disease remains a long-term debilitating and life-threatening condition that is associated with a reduced life expectancy if left untreated.

The sponsor provided updated information on the prevalence of Gaucher disease based on data from Orphanet (2013), the ICGG Gaucher registry and from the scientific literature. On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of Gaucher disease remains below the ceiling for orphan designation, which is 5 people in 10,000. At the time of the review of the orphan designation, the prevalence was still estimated to be approximately 0.3 people in 10,000. This is equivalent to a total of around 15,000 people in the EU.

At the time of the review of the orphan designation, three medicines, Cerezyme (imiglucerase), Vpriv (velaglucerase alfa) and Zavesca (miglustat), were authorised for the treatment of Gaucher disease in the EU. Cerezyme and Vpriv are ‘enzyme replacement therapies’ that work by replacing the missing enzyme. Zavesca is used as a second-line treatment in Gaucher disease patients who cannot receive enzyme replacement therapy.

The COMP concluded that the claim of a significant benefit of Cerdelga over enzyme replacement therapies is justified on the basis of its major contribution to patients’ care. This is because Cerdelga is to be taken by mouth, which is more convenient for patients with long-term disease than enzyme replacement therapies, which are given as a drip into a vein.

Comparing Cerdelga with Zavesca, the COMP noted that Zavesca can only be used in patients who cannot receive enzyme replacement therapy.

Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Cerdelga is of significant benefit to patients affected by Gaucher disease.

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Cerdelga still meets the criteria for designation as an orphan medicinal product and that it should remain in the Community Register of Orphan Medicinal Products.